This project that has the goal of identifying novel mechanisms of asthma pathogenesis, as well as new treatment approaches for patients with severe disease. The project will utilize murine models of allergic asthma to achieve these goals. Distinct sets of corticosteroid-unresponsive genes modulate disease severity in severe asthma that is refractory to corticosteroid therapy. We hypothesized that the identification of corticosteroid-unresponsive genes may provide new insights into disease pathogenesis and identify novel therapeutic approaches for asthmatic patients. Genome-wide profiling of the lung transcriptome from a clinically relevant, house dust mite (HDM) challenge model of asthma identified the up-regulated expression of apolipoprotein E (apoE), which remained persistently elevated despite treatment with corticosteroids. This lead to the identification of an apoE LDL receptor (LDLR) pathway as an endogenous negative regulator of AHR and goblet cell hyperplasia in asthma (Apolipoprotein E Negatively Regulates House Dust Mite-induced Asthma via a LDL Receptor-mediated Pathway. Yao X, Fredriksson K, Yu ZX, Xu X, Raghavachari N, Keeran KJ, Zywicke GJ, Kwak M, Amar MJ, Remaley AT, Levine SJ. Am J Respir Crit Care Med. 2010 Jul 9. Epub ahead of print). In particular, we showed that apoE is expressed by lung macrophages and negatively regulates airway hyperreactivity and goblet cell hyperplasia via a LDL receptor-dependent mechanism. Furthermore, we showed that these effects are mediated via LDL receptors that are expressed by ciliated airway epithelial cells. This genome-wide analysis of the lung transcriptome in asthma has identified additional steroid-unresponsive genes that are not known to have a role in asthma. Ongoing studies are using mice with targeted deletions in these candidate corticosteroid-unresponsive genes to define the role of these candidate genes in the pathogenesis of asthma.